Natural polymorphisms in the protease gene modulate the replicative capacity of non-B HIV-1 variants in the absence of drug pressure

Abstract Background Virological failure (VF) to boosted PIs with a high genetic barrier is not usually linked to the development of resistance-associated mutations in the protease gene. Methods From a cohort of 520 HIV-infected subjects treated with lopinavir/ritonavir or darunavir/ritonavir monotherapy, we retrospectively identified nine patients with VF. We sequenced the HIV-1 Gag-protease region and generated clonal virus from plasma samples. We characterized phenotypically clonal variants in terms of replicative capacity and susceptibility to PIs. Also, we used VESPA to identify signature mutations and 3D molecular modelling information to detect conformational changes in the Gag region. Results All subjects analysed harboured Gag-associated polymorphisms in the absence of resistance mutations in the protease gene. Most Gag changes occurred outside Gag cleavage sites. VESPA analyses identified K95R and R286K (P < 0.01) as signature mutations in Gag present at VF. In one out of four patients with clonal analysis available, we identified clonal variants with high replicative capacity and 8- to 13-fold reduction in darunavir susceptibility. These clonal variants harboured K95R, R286K and additional mutations in Gag. Low susceptibility to darunavir was dependent on the Gag sequence context. All other clonal variants analysed preserved drug susceptibility and virus replicative capacity. Conclusions Gag mutations may reduce darunavir susceptibility in the absence of protease mutations while preserving viral fitness. This effect is Gag-sequence context dependent and may occur during boosted PI failure.

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Multiple Mutations in the Human Immunodeficiency Virus Protease Gene Are Responsible for Decreased Susceptibility to Protease Inhibitors

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029500600202 ◽

1995 ◽

Vol 6 (2) ◽

pp. 80-88 ◽

Cited By ~ 21

Author(s):

R. W. King ◽

S. Garber ◽

D. L. Winslow ◽

C. Reid ◽

L. T. Bacheler ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Clinical Isolate ◽

Protease Gene ◽

Human Immunodeficiency Virus Protease ◽

Fold Reduction ◽

Antiretroviral Drug ◽

Immunodeficiency Virus ◽

Hiv 1

The protease (PR) of the human immunodeficiency virus (HIV) is essential for replication of the virus, and accordingly has become an attractive target for the development of an antiretroviral drug. We have previously reported that passage of HIV-1 in the presence of increasing concentrations of the C-2 symmetrical, linear diol P9941 resulted in the isolation of virus with a valine-to-alanine change at position 82 (V82A) of the PR, and reduced sensitivity to certain PR inhibitors. In this study, we passaged four different variants of HIV-1 in increasing concentrations of XM323, and isolated variants with reduced sensitivity to inhibitors of PR. Twenty-three passages of HIV-1 (RF) in the presence of XM323 resulted in a variant that exhibited an approximately 100-fold reduction in susceptibility to XM323 and that contained V82F and I84V changes. When two other viruses, HIV-1 (RF41D2) and HIV-1(RF41E4), previously derived from HIV-1 (RF) by passage in the presence of P9941, were passaged in the presence of XM323, variants with V82A/L97V and M46L/V82A/L97V changes, respectively, were obtained. The M46L/V82A/L97V variant showed a 6-fold reduction in sensitivity to XM323, whereas the susceptibility of the V82A/L97V mutant remained unchanged. Seventeen passages of a clinical isolate of HIV-1, HIV-1 (Pat.E), in the presence of XM323 produced a V82F/L97V mutant with an approximately 9-fold reduction in sensitivity to XM323.

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Pradimicin A, a Carbohydrate-Binding Nonpeptidic Lead Compound for Treatment of Infections with Viruses with Highly Glycosylated Envelopes, Such as Human Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.01404-06 ◽

2006 ◽

Vol 81 (1) ◽

pp. 362-373 ◽

Cited By ~ 77

Author(s):

Jan Balzarini ◽

Kristel Van Laethem ◽

Dirk Daelemans ◽

Sigrid Hatse ◽

Antonella Bugatti ◽

...

Keyword(s):

Molecular Weight ◽

Human Immunodeficiency Virus ◽

Prolonged Exposure ◽

Glycosylation Site ◽

Carbohydrate Binding ◽

Genetic Barrier ◽

Drug Pressure ◽

Immunodeficiency Virus ◽

Virus Strains ◽

Hiv 1

ABSTRACT Pradimicin A (PRM-A), an antifungal nonpeptidic benzonaphtacenequinone antibiotic, is a low-molecular-weight (molecular weight, 838) carbohydrate binding agent (CBA) endowed with a selective inhibitory activity against human immunodeficiency virus (HIV). It invariably inhibits representative virus strains of a variety of HIV-1 clades with X4 and R5 tropisms at nontoxic concentrations. Time-of-addition studies revealed that PRM-A acts as a true virus entry inhibitor. PRM-A specifically interacts with HIV-1 gp120 and efficiently prevents virus transmission in cocultures of HUT-78/HIV-1 and Sup T1 cells. Upon prolonged exposure of HIV-1-infected CEM cell cultures, PRM-A drug pressure selects for mutant HIV-1 strains containing N-glycosylation site deletions in gp120 but not gp41. A relatively long exposure time to PRM-A is required before drug-resistant virus strains emerge. PRM-A has a high genetic barrier, since more than five N-glycosylation site deletions in gp120 are required to afford moderate drug resistance. Such mutated virus strains keep full sensitivity to the other known clinically used anti-HIV drugs. PRM-A represents the first prototype compound of a nonpeptidic CBA lead and, together with peptide-based lectins, belongs to a conceptually novel type of potential therapeutics for which drug pressure results in the selection of glycan deletions in the HIV gp120 envelope.

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Association between Serum Neopterin Concentrations and In Vitro Replicative Capacity of HIV-1 Isolates

The Journal of Infectious Diseases ◽

10.1093/infdis/160.4.724 ◽

1989 ◽

Vol 160 (4) ◽

pp. 724-725 ◽

Cited By ~ 9

Author(s):

D. Fuchs ◽

J. Albert ◽

B. Asjo ◽

E. M. Fenyo ◽

G. Reibnegger ◽

...

Keyword(s):

Replicative Capacity ◽

Serum Neopterin ◽

Hiv 1

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In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 2 with Decreased Susceptibility to Lopinavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00146-07 ◽

2007 ◽

Vol 51 (9) ◽

pp. 3075-3080 ◽

Cited By ~ 20

Author(s):

Sherie Masse ◽

Xiaozhi Lu ◽

Tatyana Dekhtyar ◽

Liangjun Lu ◽

Gennadiy Koev ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

In Vitro Selection ◽

Substantial Reduction ◽

Protease Gene ◽

Infectious Clones ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2MS and HIV-2CBL-23) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2CDC310319. Passage of HIV-2MS with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2ROD molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.

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